MDT-637 is an active pharmaceutical ingredient (API) (chemical name: phenol, 2,2′-[(4-hydroxyphenyl)methylene]bis[4-[[(5-methyl-1H-tetrazol-1-yl)imino]methyl]]; alternate name: 5,5′-Bis[1-(((5-methyl-1-H-tetrazolyl)imino)methyl)]-2,2′,4″-methylidyne trisphenol; molecular formula C25H22N10O3) as described by the following structure:

MDT-637 exhibits an antiviral therapeutic activity as described in U.S. Pat. No. 6,495,580 which is hereby incorporated by reference. In addition, U.S. patent application Ser. No. 10/524,162 and U.S. patent application Ser. No. 10/524,313 describe related compounds and compositions and are also incorporated by reference. MDT-637 is associated with preventing and treating viral infections, and the diseases associated therewith, particularly those viral infections and diseases caused by viruses of the order Paramyxoviridae, including Paramyxovirinae and Pneumovirinae subfamilies.
A number of important human diseases are caused by Paramyxoviruses, including mumps, measles, and respiratory syncytial virus (RSV), which is a major cause of bronchiolitis and pneumonia in infants and children both in the US and worldwide. The mechanism of action of MDT-637 has been elucidated in some detail, and though not wishing to be bound by the following theory, it is thought that MDT-637 acts by targeting and blocking the viral fusion protein, which is a target for RSV treatments. In addition to being highly potent (40,000 times more potent than ribavirin) MDT-637 also showed that it was effective in reducing RSV viral count both pre- and post-infection.
The family Paramyxoviridae is composed of a diverse group of viruses and is divided into two subfamilies, Paramyxovirinae and Pneumovirinae.
The major human viruses of the Paramyxoviridae family are: measles virus, mumps virus, the parainfluenza viruses (types 1, 2, 3, 4a, and 4b), and respiratory syncytial virus (RSV). All of the viruses of the Paramyxoviridae family are spread through the respiratory route and are highly contagious. A number of important human diseases are caused by paramyxoviruses. These include mumps, measles, which caused 745,000 deaths in 2001 and respiratory syncytial virus (RSV), which is a major cause of bronchiolitis and pneumonia in infants and children both in the US and worldwide.
Paramyxoviruses are also responsible for a range of diseases in other animal species, for example canine distemper virus (dogs), phocine distemper virus (seals), cetacean morbillivirus (dolphins and porpoises) Newcastle disease virus (birds), and rinderpest virus (cattle). Some paramyxoviruses such as the henipaviruses are zoonotic pathogens, occurring naturally in an animal host, but also able to infect humans. Also included are certain “unassigned” viruses, such as Atlantic salmon paramyxovirus, Beilong virus, J virus, Pacific salmon paramyxovirus, and Tailam virus.
The parainfluenza viruses are the second most common causes of respiratory tract disease in infants and children. They can cause pneumonia, bronchitis and croup in children and the elderly. Infection with parainfluenza viruses typically produce minor upper respiratory tract infections which are characterized by coryza, pharyngitis, low fever, and bronchitis. Parainfluenza viruses are also the most common cause of croup, or laryngotracheobronchitis, in children aged 6 months to 5 years.
Human RSV, the prototypic member of the pneumovirus group, is the major pediatric viral respiratory tract pathogen, causing pneumonia and bronchiolitis in infants and young children. According to the US National Institutes of Health, human RSV infection, the single most important cause of severe respiratory illness in infants and young children and the major cause of infantile bronchiolitis, is the most frequent cause of hospitalization of infants and young children in industrialized countries. In the USA alone, from 85,000 to 144,000 infants with RSV infection are hospitalized annually, resulting in 20%-25% of pneumonia cases and up to 70% of bronchiolitis cases in the hospital. Global RSV disease burden is estimated at 64 million cases and 160,000 deaths every year.
Children who experience RSV infection early in life run a high risk of subsequent recurrent wheezing and asthma, especially premature infants and infants with bronchopulmonary dysplasia, for whom preventive passive immunization with anti-RSV monoclonal antibodies such as Palivizumab is highly recommended. RSV also is a significant problem in the elderly, in persons with cardiopulmonary diseases and in immunocompromized individuals. RSV attack rates in nursing homes in the USA are approximately 5%-10% per year with a 2%-8% case fatality rate, amounting to approximately 10,000 deaths per year among persons older than 64 years of age.
Attempts to develop vaccines for RSV are ongoing, but none have yet been demonstrated to be safe and efficacious. Vaccine development has been shadowed by adverse reactions exhibited by the initial formalin-inactivated RSV vaccine introduced in the late 1960s. Immunized children showed an increased incidence of RSV lower respiratory tract disease and developed abnormally severe illnesses, including death. Chemotherapy with ribavirin [1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide], an antiviral nucleoside which is the only pharmaceutical approved by the U.S. Food and Drug Administration (FDA) for treatment of RSV disease, is considered only for certain RSV patients (e.g., those at high risk for severe complications or who are seriously ill with this infection). However, its efficacy and value are controversial. Recent studies have reported a failure to demonstrate either clinical or economic benefit to patients of ribavirin treatment. Moreover, ribavirin has certain toxic side-effects and, in order to minimize these, strict administrative procedures in a closed environment must be followed.
A human intravenous immune globulin (IVIG) preparation is licensed for prophylactic use in certain patients at high-risk for RSV disease. Administration of this drug requires intravenous infusion of a large volume over a 2 to 4 hour period in children who have limited venous access due to prior intensive therapy, as well as compromised cardiopulmonary function. Moreover, intravenous infusion necessitates monthly hospital visits during the RSV season, which in turn places children at risk of nosocomial infections.
None of the above-described regimens satisfies the need for effective vaccines or therapeutics for RSV infection. Given the high risk of occurrence, along with the high incidence of mortality amongst vulnerable populations (pediatric, immunocompromised, elderly), there is a clear need for novel and effective therapeutic regimens that can alleviate and eliminate the complications associated with pneumovirus infections.
As described above, there is a wide array of infections associated with Paramyxovirinae and Pneumovirinae pathogens, and accordingly, it is evident that there exists a need for improved therapeutic regimens that can alleviate and eliminate complications associated with infection. Currently, no such therapeutics are available. In particular, a need exists for new anti-viral agents and treatments for RSV infection that overcome the shortcomings of existing pharmaceutical preparations.
MDT-637 is recognized as an effective antiviral compound, but there continues to be a need for improved compositions having desirable therapeutic characteristics such as modes of delivery and optimized distribution allowing effective and safe dosing. In addition, there is a need for compositions with beneficial physical and chemical properties, stability and handling characteristics. Furthermore, there is need for novel and consistently predictable methods of manufacturing, thereby reducing the potential for heterogeneous compositions.